The long term goal of this proposal is to investigate whether peripheral tissue insulin insensitivity exists in non ketoacidotic diabetes mellitus and to study pathophysiologic mechanisms leading to alterations in insulin action. These studies center primarily in the following questions: a) When compared with normal individuals whose tissues have been made locally hyperglycemic (in a forearm perfusion system), will diabetics have decreased forearm muscle and adipose tissue sensitivity to exogenous insulin? b) Will prolonged, low grade, systemic hyperinsulinism (a net increase of 7 to 15 uu/ml have significant effects upon endogenous and exogenous insulin sensitivity? c) Does hypergluconemia alone alter peripheral adipose and muscle tissue metabolism, and will such increases in glucagon alter insulin sensitivity? Secondary questions raised by data generated during the course of these studies include: a) Do obese subjects retain the ability to alter insulin sensitivity in the face of experimental augmentation of their already present hyperinsulinism? b) Is there evidence for autoregulation of insulin secretion during low grade systemic hyperinsulinism produced by constant insulin infusion? c) Does hyperinsulinism per se have adverse effects upon amino acid metabolism? d) Will glucagon suppression by glucose in diabetes revert to normal in diabetics when euglycemia is maintained in the post absorbtive state? e) In view of the potency of insulin upon membrane-flux of potassium, is such an alteration of membrane potential primary in the sequence of events that results in insulin action? f) Are the alterations in glucose uptake seen with glucagon perfusion secondary to alterations in lipolysis? During the course of the above forearm perfusion experiments it has also been possible to examine steroid metabolism across forearm muscle and adipose tissue using tracer methods and concurrent steroid infusion in the opposite arm. Such studies in steroid physiology will be elaborated using the forearm technique.